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Men who used the erectile-function drug sildenafil (Viagra) had almost twice the risk of melanoma compared with men who never used the drug, researchers found.

Note that sildenafil use did not influence the risk of squamous-cell or basal-cell skin cancer.

Men who used the erectile-function drug sildenafil (Viagra) had almost twice the risk of melanoma compared with men who never used the drug, a study of 26,000 men showed.

Recent sildenafil use was associated with an 84% greater risk of melanoma. Use of the drug had no association with the risk of nonmelanoma skin cancers, according to Jiali Han, PhD, of the Indiana University School of Public Health in Indianapolis, and co-authors. Moreover, erectile function per se did not correlate with melanoma risk, they reported in JAMA Internal Medicine.

"Our study cannot prove cause and effect," the authors concluded. "A longer follow-up and more detailed assessment of the dose and frequency of sildenafil use at multiple times in the [study cohort] would be necessary for future studies."

Though just an association -- not proof of causality -- the link between sildenafil and melanoma does have a potential molecular basis, said Ryan Sullivan, MD, of Massachusetts General Hospital in Boston.

"Sildenafil may promote tumor growth, at least in tumor cells," Sullivan told MedPage Today. "There's plausibility, but this not causation as of yet. There's still a lot of work that needs to be done before we can definitively say that drugs for erectile dysfunction cause melanoma."

If the association proves to be a real relationship, then the effect on melanoma risk probably applies to all drugs in the PDE5-inhibitor class, he added.

The underlying biologic mechanisms of melanoma involve multiple molecular entities within a complex signaling pathway. Mutations in BRAF occur in about half of all melanomas. Drugs that target BRAF have demonstrated efficacy in the treatment of melanoma.

Recently, the enzyme phosphodiesterase 5A (PDE5A) was reported to be a downstream target of BRAF, the authors noted. Activated BRAF downregulates PDE5A to facilitate invasion and metastasis of melanoma cells. Additionally, other molecules in the melanoma-associated signaling pathway, notably NRAS, have been shown to downregulate PDE5A in melanoma cell lines.

"This indicates that PDE5A suppression by sildenafil use mimics an effect of BRAF/NRAS activation and thus may potentially function as one of the 'hits' for melanomagenesis," according to the authors' background information.

Two PDE5 inhibitors have been shown to promote melanin synthesis, which may stimulate melanoma development, they continued. The body of evidence led Han and colleagues to hypothesize the existence of an association between sildenafil use and melanoma.

To test the hypothesis, investigators analyzed data from the Health Professionals Follow-up Study (HPFS), which began in 1986 and has a total enrollment of 51,529 male health professionals ages 40 to 75. Each participant completed a health survey at baseline and then every 2 years.

In the 2000 follow-up survey, HPFS participants were asked whether they had undergone surgery or received other treatment for erectile dysfunction within the previous 3 months. With respect to sildenafil use, respondents were not asked to provide specific information about drug dosage or frequency of use.

The 2000 survey also included items related to erectile function before 1986, and from 1986 to 1986, 1990 to 1994, and 1995 to 2000, as well as during the past 3 months. Men who reported poor or very poor erectile function at or before 2000 were considered to have erectile dysfunction in 2000.

The HPFS questionnaires also included items related to risk factors for melanoma, such as hair color and skin type, number of lifetime sunburns, moles on the arms, state of residence at birth and at 15 and 30, and tendency to sunburn during adolescence.

Family history of melanoma was included in the 1990 and 1992 surveys. In 2008, the survey included items related to midday sun exposure at ages from high school to 60. Every biennial survey collected information about smoking, body mass index, and physical activity.

Men who completed the 2000 HPFS questionnaire provided the study population. Investigators excluded participants who had diagnoses of squamous-cell skin cancer, basal-cell skin cancer, or melanoma prior to 2000. Follow-up continued to the last completed questionnaire or the 2010 questionnaire, whichever came first.

The analysis included 25,848 men who had a mean baseline age of 64.8. The authors found that 5.3% of the men reported recent use of sildenafil, and 6.3% reported any use.

Sildenafil users tended to:

Be older and obese

Have a history of severe and blistering sunburns

Be more likely to undergo physical examinations

Be exposed to less sunlight as adults

From 2000 to 2010, 142 melanoma diagnoses were documented, as were 580 cases of squamous-cell skin cancer and 3,030 cases of basal-cell skin cancer.

In a multivariate analysis, men who reported current sildenafil use at baseline had a melanoma hazard ratio of 1.84 versus men who had never used the drug (95% CI 1.04-3.22). Men who reported any use of sildenafil had a similar melanoma risk (HR 1.94, 95% CI 1.14-3.22).

In contrast, sildenafil use did not influence the risk of squamous-cell or basal-cell skin cancer.

The increased risk of melanoma persisted among sildenafil users after exclusion of patients who had major comorbidities at baseline, including in increased risk with recent use (HR 2.24, 95% CI 1.05-4.78) and any use (HR 2.77, 95% I 1.32-5.85).

The study was supported in part by the National Institutes of Health.

The authors disclosed no relevant relationships with industry.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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